1086 IMPURITIES IN OFFICIAL ARTICLES
This general information chapter covers impurities or degradation products in drug substances and degradation products in drug products. Impurities or degradation products in drug substances can arise during the manufacturing process or during storage of the drug substance. The degradation products in drug products can arise from drug substances or reaction products of the drug substance with an excipient or an immediate containerclosure system. Biological, biotechnological, and radiopharmaceutical products are not covered in this chapter.
Concepts about purity change with time and are inseparable from developments in analytical chemistry. If a material previously considered to be pure can be resolved into more than one component, that material can be redefined into new terms of purity and impurity. Inorganic, organic, biochemical, isomeric, or polymeric components can all be considered impurities. Microbiological species or strains are sometimes described in similar terms of resolving into more than one component.
Communications about impurities or degradation products in compendial articles may be improved by including in this Pharmacopeia the definitions of terms and the contexts in which these terms are used. (See Definitions below.) There has been much activity and discussion in recent years about term definition. Certain industry-wide concerns about terminology and context deserve widespread publication and ready retrievability and are included here. See Foreign Substances and Impurities in the section Tests and Assays under General Notices and Requirements, as well as the general chapter Ordinary Impurities 466. Some other general chapters added over the years have also addressed topics of purity or impurity as these have come into focus or as analytical methodology has become available. Analytical aspects are enlarged upon in the chapter Validation of Compendial Procedures 1225.
Monographs for drug substances usually cite one of three types of purity tests: (1) a chromatographic purity test coupled with a nonspecific assay; (2) a chromatographic purity-indicating method that serves as the assay; or (3) a specific test and limit for a known impurity, an approach that usually requires a Reference Standard for that impurity. Modern separation methods clearly play a dominant role in scientific research today because these methods simultaneously separate and measure components and fulfill the analytical ideal of making measurements only on purified specimens. Nevertheless, the more classical methods based on titrimetry, colorimetry, spectrophotometry, single or multiple partitions, or changes in physical constants (or any other tests or assays) lose none of their previous validities. The purity profile of a specimen that is constructed from the results of experiments using a number of analytical methods is the ultimate goal.
Purity or impurity measurements for drug products present a challenge to Pharmacopeial standards-setting. Where degradation of a drug product over time is at issue, the same analytical methods that are stability-indicating are also purity-indicating. Resolution of the active ingredient(s) from the excipients necessary to the preparation presents the same qualitative problem. Thus, many monographs for Pharmacopeial preparations feature chromatographic assays. Where more significant impurities are known, some monographs set forth specific limit tests. In general, however, this Pharmacopeia does not repeat impurity tests in subsequent preparations where these appear in the monographs of drug substances and where these impurities are not expected to increase. It is presumed that adequate retention specimens are in storage for the exact batch of drug substances used in any specific lot of a drug product. Whenever analysis of an official article raises a question of the official attributes of any of the drug substances used, subsequent analysis of retention specimens is in order.
Pharmaceutical manufacturers interact with regulatory agencies in developing new drug substances and new drug products, and cooperate with the compendia in writing official monographs for the compendial articles the manufacturers produce. Establishment of impurity limits in drug substances and drug products should proceed on a rational basis so that everyone involved in the development and approval phases can carry on their work in a predictable manner. Although drug development in the United States is the primary focus of this section of the chapter, the subject also has broad applicability across national boundaries.
Manufacturers share with regulatory agencies and with the compendia the goal of making available to the public high-quality products that are both safe and efficacious. This goal continues to be achieved through rational approaches to the complex process of drug development. Tests used at all stages of drug development and marketing should not be interpreted individually but as a whole. Controls on raw materials and on manufacturing as well as those on drug substances, along with toxicological and clinical studies performed, ensure the safety and efficacy of drug products. It is more rational to identify impurities or degradation products and to set limits based on the factors detailed here, relying on the scientific judgments of manufacturers, the compendia, and regulators to arrive at sets of acceptable limits for identified and unidentified impurities or degradation products.
Limits are set for impurity levels or degradation products as one of the steps in ensuring the identity, strength, quality, and chemical purity of drug substances or drug products. The ultimate goal is to produce a final drug product of high quality that is safe and efficacious and remains so throughout its shelf life. The setting of limits for impurities or degradation products in drug substances is a complex process that considers a number of factors:
Concepts for setting impurity or degradation product limits in drug substances are based on chemistry and safety concerns. As such, limits for organic and inorganic impurities and residual solvents should be established for drug substances. The basic tenet for setting limits is that levels of impurities or degradation products in a drug substance must be controlled to ensure its safety and quality throughout its development to use in a drug product.
For drug products the concept for setting degradation product limits is based on sound scientific judgment as applied to available data on the safety and stability of the drug product, which may include the degradation pathways of the drug substance, the manufacturing process, known excipient interactions, any safety assessment studies, stability studies conducted under the recommended storage conditions, and ancillary studies that may provide additional information on the stability profile of the drug product. A rationale should be provided for exclusion of those impurities that are not degradation products (e.g., process impurities from drug substance and impurities arising from excipients).
For drug substances and drug products, limits are appropriately set no higher than the level that can be justified (e.g., safety data, literature references, etc.) and no lower than the level achievable by the manufacturing process and analytical capability. Where there is no safety concern, limits should be based on (a) data generated on actual batches of the drug substance or drug product, allowing sufficient latitude to deal with normal process and analytical variation, and (b) stability characteristics.
Documented evidence that the analytical procedure used to evaluate impurities or degradation products is validated and suitable for the detection and quantification of impurities or degradation products should be established.
The setting of limits on impurities or degradation products is an evolutionary process, beginning in the United States before an investigational new drug (IND) is filed and continuing until well after the approval of a new drug application (NDA). Therefore, it is appropriate to address different stages in drug development as separate issues. There are three points in the drug development process where the setting of limits may be significantly different: (1) at the initial IND application, (2) at the filing of the NDA, and (3) after NDA approval. The filing of an abbreviated new drug application (ANDA) is another activity in which limits are set on impurities or degradation products. Since the approach may vary from that of filing an NDA, it is addressed as a separate issue. The underlying assumption is that the analytical methods used to evaluate impurities or degradation products are suitable for their intended purpose at each stage in the development.
INITIAL IND FILING
Drug Substances At the initial IND filing, the chemical nature of a drug substance has generally been defined. The manufacturing process normally is in an early stage of development, and materials may be produced on a laboratory scale. Usually few batches have been made and, therefore, little historical data is available. The reference materials of a drug substance may be relatively impure. Limits for the purity of a drug substance are set to indicate drug quality. The setting of limits on related substances and process contaminants can be characterized as follows.
Although water is not classified as an impurity, limits for water content may be needed to ensure the stability or ease of processing a drug substance.
Drug Product At the initial IND filing, the dosage form of a drug product has been identified, which is appropriate for early clinical studies (and may or may not be representative of the drug product that will eventually be marketed). Usually, few batches have been made and, therefore, little historical data is available.
Drug Substances During the IND phases of drug development, the manufacturing process for a drug substance may undergo a number of revisions. Generally, the scale will have changed from laboratory size and will approach or reach full production batch size. A number of batches will normally have been produced, and a historical data base of the results of testing for impurities will exist. When significant changes in a manufacturing process are made, the impurity profile should be reviewed to determine if the toxicological studies are still supportive.
At the NDA stage a reference standard of defined purity is available, analytical methods have been validated, impurity and degradation profiles are known, and enantiomeric purity has been evaluated. The setting of limits on related substances and process contaminants can be characterized as follows.
Drug Product Similarly, for the drug product, the dosage form may change, the number or scale of batches may increase, and more stability data will have become available. Methods will have been validated. The setting of limits can be characterized as follows:
POST NDA APPROVAL
After approval and marketing of a pharmaceutical product, significant changes may be made in manufacturing the drug substance. There may be technological, ecological, economic, or safety reasons for these changes. If they occur, the Pharmacopeial and NDA impurity and degradation product limits and rationale should be reviewed; the limits should be revised when indicated to ensure similar or improved quality of the drug substance or drug product.
The drug substance for a pharmaceutical product eligible for ANDA status is frequently an official article and should be well characterized analytically. Drug substances are typically available from multiple sources, and each source may have a different manufacturing process. Therefore, it is essential that the dosage form manufacturer evaluate each supplier's drug substance impurity or degradation profiles. Limits can then be set based on the more detailed concepts described for NDA filing, including review of compendial monographs for appropriateness.
Concomitant Components Concomitant components are characteristic of many drug substances and are not considered to be impurities in the Pharmacopeial sense. Limits on contents, or specified ranges, or defined mixtures are set forth for concomitant components in this Pharmacopeia. Examples of concomitant components are geometric and optical isomers (or racemates) and antibiotics that are mixtures. Any component that can be considered a toxic impurity because of significant undesirable biological effect is not considered to be a concomitant component.
Foreign Substances (Extraneous Contaminants) Foreign substances (extraneous contaminants), which are introduced by contamination or adulteration, are not consequences of the synthesis or preparation of compendial articles and thus cannot be anticipated when monograph tests and assays are selected. The presence of objectionable foreign substances not revealed by monograph tests and assays constitutes a variance from the official standard. Examples of foreign substances include ephedrine in Ipecac or a pesticide in an oral liquid analgesic. Allowance is made in this Pharmacopeia for the detection of foreign substances by unofficial methods. (See Foreign Substances and Impurities in the section Tests and Assays under General Notices and Requirements.)
Identified Impurities and Identified Degradation Products Impurities or degradation products for which structural characterizations have been achieved.
Inorganic Impurities Inorganic impurities can result from the manufacturing process (e.g., residual metals, inorganic salts, filter aids, etc.). Inorganic impurities are typically controlled by tests such as Heavy Metals 231 and Residue on Ignition 281. Information found in Plasma Spectrochemistry 730 and Ion Chromatography 1065 may also be of value.
Ordinary Impurities Some monographs make reference to ordinary impurities. For more details see Ordinary Impurities 466.
Process Contaminants Process contaminants are identified or unidentified substances (excluding related substances and water), including reagents, catalysts, other inorganic impurities (e.g., heavy metals, chloride, or sulfate); and may also include foreign substances (extraneous contaminants). These contaminants may be introduced during manufacturing or handling procedures.
Related Substances Related substances are structurally related to a drug substance. These substances may be (a) identified or unidentified impurities arising from synthesis manufacturing process such as intermediates or by-products and do not increase on storage or (b) identified or unidentified degradation products that result from drug substance or drug product manufacturing processes or arise during storage of a material.
Residual Solvents Refer to Residual Solvents 467.
Specified Impurities and Specified Degradation Products Previously referred to as Signal Impurities, specified impurities or specified degradation products are impurities or degradation products that are individually listed and limited with specific acceptance criteria in individual monographs as applicable. Specified impurities or specified degradation products can be identified or unidentified.
Toxic Impurities Toxic impurities have significant undesirable biological activity, even as minor components, and require individual identification and quantification by specific tests. These impurities may arise out of the synthesis, preparation, or degradation of compendial articles. Based on validation data, individualized tests and specifications are selected. These feature comparison to a Reference Standard of the impurity, if available. It is incumbent on the manufacturer to provide data that would support the classification of such impurities as toxic impurities.
Unidentified Impurities and Unidentified Degradation Products Impurities or degradation products for which structural characterizations have not been achieved and that are identified solely by qualitative analytical properties (e.g., chromatographic retention times).
Unspecified Impurities and Unspecified Degradation Products Impurities or degradation products that are limited by general acceptance criteria but not individually listed with their own specific acceptance criteria in individual monographs.
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